The systemic vasculitides include a variety of generalized, life-threatening autoimmune diseases that have been studied for more than 30 years at the National Institutes of Allergy and Infectious Diseases. During this time large numbers of patients have been analyzed with regard to disease classification, pathophysiology, and treatment. We have previously demonstrated that the use of daily cyclophosphamide (CP) and glucocorticoids (GC) is highly effective therapy for Wegener?s granulomatosis (WG). These studies pioneered the use of low-dose cytotoxic therapy as a treatment for life-threatening autoimmune diseases and our therapeutic protocol is used throughout the world. However, drug toxicity has limited use of this regimen in many patients. Thus, a major focus of this project has been to develop less toxic therapeutic regimens for the treatment of WG and related systemic vasculitis syndromes. Our approach to achieving this objective initially involved conducting a series of clinical trials that utilized less toxic conventional immunosuppressive regimens to induce and maintain remission. We have evaluated the safety and efficacy of methotrexate (MTX) as an alternative therapy for WG. Results indicate that low-dose weekly MTX is acceptable initial therapy for selected patients with WG who do not have immediately life-threatening disease and represents a less toxic alternative to standard CP therapy in this group of patients. We have also investigated the potential for MTX to be used as maintenance therapy in patients in whom CP has induced a disease remission. We have demonstrated that a cyclophosphamide induction-MTX maintenance regimen is highly effective and represents a less toxic alternative to the standard cyclophosphamide regimen for patients with severe disease. We have also explored the use other immunosuppressive drugs as remission maintenance agents. In a small open-label trial we investigated whether the immunosuppressive agent mycophenolate mofetil, could be used in place of MTX for maintenance of CP-induced remission in patients with WG. Preliminary results of this study indicated that mycophenolate mofetil appeared to have efficacy in maintaining remission following CP therapy. As a direct result of these studies, physicians now have available to them effective, less toxic regimens to use in the treatment of patients with WG. The increasing availability of biologic agents that modulate specific aspects of the immune response may soon make it possible to treat systemic vasculitis syndromes by selectively targeting pathogenic inflammation while leaving global host defense mechanisms intact. Along these lines, we are currently conducting two clinical trials in WG that employ specific cytokine antagonists. The first of these trials is designed to assess the safety, efficacy, and immunologic effects of a recombinant fusion protein that contains the extra cellular portion of the p75 TNF receptor linked to the Fc portion of human IgG1 (Etanercept). We are seeking to examine whether Etanercept is able to reduce the need for glucocorticoid treatment and lower relapse rates in patients with WG. The second trial will investigate the safety and efficacy of Daclizumab (a humanized monoclonal antibody that blocks the high-affinity interleukin-2 receptor on T cells) in the treatment of WG. This trial will seek to determine the efficacy of Daclizumab in preventing disease relapses. In addition to our studies in WG we recently initiated a phase I/II trial that will assess the safety and efficacy of Rituximab (a B cell depleting monoclonal antibody) in the treatment of patients with hepatitis C associated cryoglobulinemic vasculitis (HCV-CV). This disease occurs when an aberrant immune response to chronic HCV infection generates on oligoclonal expansion of B cells that produce IgM rheumatoid factor. The production of IgM rheumatoid factor leads to the formation of immune complexes consisting of HCV antigens, polyclonal HCV-specific IgG, and IgM rheumatoid factor. The deposition of these immune complexes in blood vessel walls triggers an inflammatory cascade that results in vasculitis. For the majority of patients with this disease there is no effective therapy. This protocol will test the hypothesis that treatment with Rituximab will deplete the oligoclonal population of B cells that are producing the pathogenic IgM rheumatoid factor that drives the immune-complex disease. Treatment with Rituximab should not alter the cell-mediated immune response to HCV, and thus should not exacerbate the liver disease.